Cardiac hypertrophy in hypertension has usually been viewed in terms of adaptation to an increased pressure load. Other factors, however, may play an important role in cardiac involvement in hypertensive diseases, as suggested by our observations that (a) increase in ventricular weight antedates hypertension in spontaneously hypertensive rats (SHR) and (b) hypertrophy could be prevented or even reversed in SHR by alpha-methyldopa but not by hydralazing even though both drugs controlled arterial pressure equally. These observations may be related to a number of factors, humoral or hemodynamic. A special relationship between renin and cardiac hypertrophy was indicated by pilot studies showing a close correlation between plasma renin activity and heart weight in renovascular hypertensive rats, in the prehypertensive phase of SHR and in treated SHR. On the other hand, hemodynamic factors other than a raised pressure may be involved, e.g. increased heart rate or output. We propose therefore an extensive study of the hemodynamic and biochemical correlates of cardiac hypertrophy in spontaneous hypertension with special emphasis on factors associated with reversibility of hypertrophy by medical treatment. Variations in cardiac weight, myocardial contractility and myocardial composition will be investigated under two sets of conditions: (1) maneuvers influencing the renin-angiotensin system with minimal interference with arterial pressure and (2) alterations of hemodynamic effects of therapy either by cardioselective Beta-adrenergic blockade or by inducing chronic tachycardia. In addition, the effect of different neural blocking drugs as well as of angiotensin analogues on myocardial protein synthesis will be investigated in both normal and hypertensive animals. Should control of the renin-angiotensin system prove a factor in preventing or reversing cardiac hypertrophy, this would be particularly important in planning antihypertensive therapy.